This Project within the PPG will investigate, using SIV and SHIV infection in rhesus macaques, the effect of[unreadable] polyamine biosynthesis inhibitors (PBI) on pathogenesis AIDS and sequela of neuroAIDS. For this, we[unreadable] initially propose to investigate the polyamine biosynthesis inhibitors PA-001 in the first 2.5 years and a[unreadable] second designated PA-002 in the last 2.5 years. We hypothesize the PBI will deactivate and/or selectively[unreadable] target populations of CD14+ and CD16+ monocyte/macrophages, some of which are SIV infected. We[unreadable] propose to use a) a CD8+ lymphocyte depletion model of SIV infection that results in rapid, consistent and[unreadable] severe CMS disease with SIV encephalitis (SIVE), and b) a SHIV infection model that rapidly depletes CD4+[unreadable] T lymphocytes resulting in high virus replication in monocyte/macrophages, to study the effects of PBI;[unreadable] deactivating and/or killing select monocyte/macrophage subsets; delaying the onset and/or reversing CNS[unreadable] disease; potentially flushing monocyte/macrophage viral reservoirs. We propose three Specific Aims to test[unreadable] our hypothesis.[unreadable] Specific Aim 1 will determine whether PBI (PA-001 and PA-002) deactivates and/or kills select CD14+CD16+[unreadable] monocyte/macrophage during: a) acute infection (7-21 days pi) and b) with the development of AIDS.[unreadable] Specific Aim 2 will test the hypothesis that PBI (PA-001 and PA-002) treatment deactivates and/or kills select[unreadable] CD14+CD16+ monocyte/macrophage populations, delaying and/or reversing the development of AIDS and[unreadable] SIVE.[unreadable] Specific Aim 3 will test the hypothesis that PBI treated, SHIV infected animals that are CD4+ T cell depleted[unreadable] and have high virus replication in monocyte/macrophages, clears or diminishes viral reservoirs in blood,[unreadable] lymphoid and CNS tissues.[unreadable] Studies proposed in this project have direct relevance to studies of human AIDS and neuroAIDS, and[unreadable] support Projects 1 and 3 of the PPG. These studies: use a well-defined primate model of neuroAIDS to[unreadable] better identify monocyte subsets that predict progression of AIDS and neuroAIDS with SIVE development;[unreadable] assess the significance of continued monocyte traffic on neuropathogenesis and CNS infection; and[unreadable] investigate the potential of select pharmacologic agents (PBI), which have been used in human clinical trials,[unreadable] to deactivate and kill SIV infected monocyte/macrophages. These studies will add to our understanding of[unreadable] the role of monocyte/macrophages in AIDS and AIDS neuropathogenesis and directly assess the utility of[unreadable] reagents for use in human clinical trials for neuroAIDS. They will adds support to proposed clinical studies in[unreadable] Project 3, and will provide dynamic sampling of blood and SIV infected tissues for Project 1, defining[unreadable] mechanisms of function of PBI. Lastly, these studies may better define the role of monocyte/macrophages[unreadable] contributing to AIDS and functioning as cellular reservoir of HIV.